WO2005113544A1 - 2-{[2-(2-méthylamino-pyrimidine-4-yl)-1h-indole-5-carbonyle]-aminé}-3-(phénylpyridine-2-yl-aminé)-acide propionique substantiellement pur comme inhibiteur de kinase ikb - Google Patents

2-{[2-(2-méthylamino-pyrimidine-4-yl)-1h-indole-5-carbonyle]-aminé}-3-(phénylpyridine-2-yl-aminé)-acide propionique substantiellement pur comme inhibiteur de kinase ikb Download PDF

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WO2005113544A1
WO2005113544A1 PCT/US2005/016381 US2005016381W WO2005113544A1 WO 2005113544 A1 WO2005113544 A1 WO 2005113544A1 US 2005016381 W US2005016381 W US 2005016381W WO 2005113544 A1 WO2005113544 A1 WO 2005113544A1
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compound
administering
ikk
effective amount
inhibitors
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PCT/US2005/016381
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English (en)
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El-Bdaoui Haddad
Olaf Ritzeler
David J. Aldous
Paul Joseph Cox
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Aventis Pharmaceuticals Inc.
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Priority to MXPA06012870A priority Critical patent/MXPA06012870A/es
Priority to CA002566213A priority patent/CA2566213A1/fr
Priority to AU2005245834A priority patent/AU2005245834A1/en
Priority to JP2007513292A priority patent/JP2007537266A/ja
Priority to BRPI0511029-7A priority patent/BRPI0511029A/pt
Priority to EP05749733A priority patent/EP1747215A1/fr
Publication of WO2005113544A1 publication Critical patent/WO2005113544A1/fr
Priority to TNP2006000338A priority patent/TNSN06338A1/en
Priority to IL178992A priority patent/IL178992A0/en
Priority to US11/559,159 priority patent/US20070142417A1/en
Priority to NO20065719A priority patent/NO20065719L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention is directed to an indole derivative, its preparation, a pharmaceutical composition comprising the compound, its use, and intermediates thereof.
  • NF- ⁇ B is a heterodimeric transcription factor that regulates the expression of multiple inflammatory genes.
  • the expression of more than 70 known proteins is transcriptionally regulated by the binding of NF- ⁇ B to specific sequence elements in the promoter region of these genes (Baeuerle and Baichwal, Advances in Immunology 65:111-137, 1997).
  • NF- ⁇ B has been implicated in many pathophysiologic processes including angiogenesis (Koch et al., Nature 376:517-519, 1995), atherosclerosis (Brand et al., J Clin Inv. 97: 1715-1722, 1996), endotoxic shock and sepsis (Bohrer et al., J. Clin. Inv.
  • IKB kinases are key regulatory signaling molecules that coordinate the activation of NF- KB.
  • TWO IKKs, IKK-1 (IKK- ) and IKK-2 (IKK- ⁇ ), are structurally unique kinases containing an N- terminal kinase domain with a dual serine activation loop, a leucine zipper domain, and a C-terminal helix-loop-helix domain and serine cluster.
  • IKK enzymes show relatively low sequence homologies with other kinases, and early profiles with known kinase inhibitors have not identified compounds with striking potency.
  • IKK-2 binds to and phosphorylates I ⁇ B ⁇ , and I ⁇ B ⁇ with high and relatively equal affinities (Heilker et al. 1999).
  • Recombinant IKK-2 phosphorylates I ⁇ B ⁇ peptide 26-42 with near equal affinity to full length IKBOC, however the native IKK enzyme complex phosphorylates full length I ⁇ B ⁇ 25,000 fold more efficiently, suggesting important regulatory sequences in the C-terminal region of I ⁇ B ⁇ , or additional regulatory proteins in the IKK enzyme complex that accelerate the rate of catalysis (Burke et al., Journal of Biological Chemistry 274:36146- 36152, 1999).
  • I ⁇ B ⁇ Phosphorylation of I ⁇ B ⁇ occurs via a random sequential kinetic mechanism, meaning either ATP or I ⁇ B ⁇ may bind first to IKK-2, that both must be bound before phosphorylation of IKBOC can take place (Peet and Li, Journal of Biological Chemistry 274:32655-32661, 1999).
  • rKK-1 and IKK-2 occur both as heterodimers and IKK-2 homodimers, and are associated with a 700- 900 kDa cytoplasmic enzyme complex called the "IKK Signalsome” (Mercurio et al., Science 278:860-866, 1997).
  • IKKAP-1 or NEMO/IKK ⁇ has no apparent catalytic function but will associate directly with IKK-2 and is necessary for full activation of NF- ⁇ B (Mercurio et al., Mol Cell Biol 19:1526-1538, 1999).
  • the IKK complex appears to be the central integrator of diverse inflammatory signals leading to the phosphorylation of IKB.
  • IKKs are activated at dual serine residues by upstream kinases including NF- KB inducing kinase, NIK (Malinin et al., Nature 385:540-544, 1997), and MEKK-1 (Yujiri et al., Science 282: 1911-1914, 1998).
  • NIK NF- KB inducing kinase
  • MEKK-1 Yujiri et al., Science 282: 1911-1914, 1998.
  • the differential activities of NIK and MEKK-1 remain unclear although initial data indicates these kinases may preferentially activate IKK-1 and IKK-2, respectively.
  • IKK Activated IKK phosphorylates a cytoplasmic inhibitor protein, I ⁇ B that binds NF- ⁇ B, thereby masking a nuclear localization signal present in Rel proteins (Cramer et al., Structure 7: R1-R6, 1999).
  • IKK phosphorylation of I ⁇ B on serines 32 and 36 forms a structural motif recognized by the E3 ligase, ⁇ TRcP (Yaron et al., Nature 396:590-594, 1998). Docking of ⁇ TRcP results in the formation of a ligase complex which polyubiquitinates I ⁇ B thus targeting it for degradation by the 26S proteosome. Free NF- ⁇ B is then identified by nuclear transport proteins, which translocate it to the nucleus where it can associate with sequence specific regulatory elements on gene promoters.
  • IKK-2 did not phosphorylate I ⁇ B in vitro
  • pro-inflammatory stimuli such as IL-l ⁇ and TNF ⁇
  • catalytically inactive mutants of IKK-2 blocked the expression of NF- ⁇ B regulated genes such as monocyte chemotactic protein (MCP-1) and intercellular adhesion molecule (ICAM-1) (Mercurio et al, Science 278:860-866, 1997).
  • MCP-1 monocyte chemotactic protein
  • IAM-1 intercellular adhesion molecule
  • IKK-2 is a central regulator of the pro- inflammatory role of NF- ⁇ B, wherein the IKK-2 is activated in response to immune and inflammatory stimuli and signaling pathways.
  • immune and inflammatory mediators including IL-l ⁇ , LPS, TNF ⁇ , CD3/CD28 (antigen presentation), CD40L, FasL, viral infection, and oxidative stress, play an important role in respiratory diseases.
  • CD40L ubiquitous expression of NF- ⁇ B, along with its response to multiple stimuli means that almost all cell types present in the lung are potential target for anti-NF- ⁇ B/IKK-2 therapy.
  • IKK-2 By inhibiting the expression of genes such as cyclooxygenase-2 and 12- lipoxygenase (synthesis of inflammatory mediators), TAP-1 peptide transporter (antigen processing), MHC class I H-2K and class II invariant chains (antigen presentation), E-selectin and vascular cell adhesion molecule (leukocyte recruitment), interleukins-1, 2, 6, 8 (cytokines), RANTES, eotaxin, GM- CSF (chemokines), and superoxide dismutase and NADPH quinone oxidoreductase (reactive oxygen species), inhibitors of IKK-2 are believed to display broad anti-inflammatory activity.
  • genes such as cyclooxygenase-2 and 12- lipoxygenase (synthesis of inflammatory mediators), TAP-1 peptide transporter (antigen processing), MHC class I H-2K and class II invariant chains (antigen presentation), E-selectin and vascular cell adhesion molecule (leukocyte recruitment), inter
  • Patent application WO 94/12478 describes, inter alia, indole derivatives that inhibit blood platelet aggregation.
  • Patent applications WO 01/00610 and WO 01/30774 describe indole derivatives and benzimidazole derivatives, which are able to modulate NF- ⁇ B.
  • NF- ⁇ B is a heterodimeric transcription factor that is able to activate a large number of genes that encode, inter alia, proinflammatory cytokines such as IL-1, IL-2, TNF ⁇ or IL-6.
  • NF- ⁇ B is present in the cytosol of cells, where it is complexed with its naturally occurring inhibitor I ⁇ B. Stimulation of the cells, for example by cytokines, leads to the IKB being phosphorylated and subsequently broken down proteolytically. This proteolytic breakdown leads to the activation of NF- ⁇ B, which then migrates into the nucleus of the cell, where it activates a large number of proinflammatory genes.
  • NF- ⁇ B is activated beyond its normal extent.
  • the inhibition of NF- ⁇ B is also described as being useful for treating cancer on its own or in addition to cytostatic therapy. Inhibition of the NF- ⁇ B -activating signal chain at various points or by interfering directly with the transcription of the gene by glucocorticoids, salicylates or gold salts, has been shown as being useful for treating rheumatism.
  • the first step in the abovementioned signal cascade is the breakdown of I ⁇ B.
  • This phosphorylation is regulated by the specific IKB kinase.
  • inhibitors of IKB kinase are known to frequently suffer from the disadvantage of being non-specific for inhibiting only one class of kinases.
  • most inhibitors of IKB kinase inhibit several different kinases at the same time because the structures of the catalytic domains of these kinases are similar. Consequently, the inhibitors act, in an undesirable manner on many enzymes, including those that possess the vital function.
  • COPD chronic obstructive pulmonary disease
  • the airflow limitation is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking.
  • COPD affects the lungs, it also produces significant systemic consequences.
  • the term COPD encompasses chronic obstructive bronchitis, with obstruction of small airways, and emphysema, with enlargement of air spaces and destruction of lung parenchyma, loss of lung elasticity, and closure of small airways.
  • Chronic bronchitis by contrast, is defined by the presence of a productive cough (due to hypersecretion of mucus) of more than three months' duration for more than two successive years.
  • mucus hypersecretion is accompanied by airflow obstruction, perhaps as a result of obstruction of peripheral airways.
  • Most patients with COPD have all three pathologic conditions (chronic obstructive bronchitis, emphysema, and mucus plugging), but the relative extent of emphysema and obstructive bronchitis within individual patients can vary, Vestbo et al., 1996; Barnes, 2004a, Barnes, 2004b; Hogg, 2004.
  • COPD patients are predisposed to exacerbations, that is, an acute worsening of their respiratory symptoms.
  • An exacerbation of COPD is an event in the natural course of the disease characterized by a change in the patient's baseline dyspnea, cough and/or sputum beyond day-to-day variability sufficient to warrant a change in management (Rodriguez-Roisin, 2000; Burge and Wedzicha, 2003).
  • type 1 exacerbations were characterized by increased breathlessness, increased sputum volume, and new or increased sputum purulence; type 2 included any two of these symptoms; and type 3 consisted of any one of the symptoms together with at least one additional feature, including sore throat or nasal discharge within the last five days; unexplained fever; increased wheeze; increased cough; or a 20% increase in respiratory or heart rate compared with baseline.
  • NF- ⁇ B The inhibition of NF- ⁇ B is also described as being useful for treating hypoproliferative diseases, e.g., solid tumor and leukemias, on its own or in addition to cytostatic therapy. Inhibition of the NF- ⁇ B- activating signal chain at various points or by interfering directly with the transcription of the gene by glucocorticoids, salicylates or gold salts, has been shown as being useful for treating rheumatism.
  • Patent application WO 01/30774 discloses indole derivatives and US Application Serial No. 10/642,970, discloses indole and benzimidazole derivatives which are able to modulate NF- ⁇ B and which exhibit a strong inhibitory effect on I ⁇ B kinase.
  • US Application Serial No. 10/642,970 discloses indole and benzimidazole derivatives of formula (I), their preparation,
  • an inhibitor of IKB kinase that operates through the selective inhibition of DCK, particularly an IKK-2 inhibitor. Also desired would be to have such an inhibitor that exhibits a localized activity as opposed to a systemic activity. Such an inhibitor should have a utility in treating a patient suffering from or subject to IKK-2 mediated pathological (diseases) conditions, e.g., asthma, or chronic obstructive pulmonary disorder (COPD), that could be ameliorated by the targeted administering of then inhibitor.
  • IKK-2 mediated pathological (diseases) conditions e.g., asthma, or chronic obstructive pulmonary disorder (COPD)
  • the present invention is directed to a compound having activity as an inhibitor, preferably a selective inhibitor, of IKB (IKK), particularly IKK-2, and to a composition and methods related thereto.
  • IKK IKB
  • the present invention is directed to the substantially pure compound of formula (A):
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically effective amount of the compound of formula (A), and a pharmaceutically acceptable carrier.
  • the present invention is directed to the use of a compound of formula (A) as an inhibitor of IKB kinase.
  • FIGURE 1 shows a picture of mouse imaging studies in the NF- ⁇ B-Luciferase Reporter Mouse Model wherein animals are treated with the Vehicle/PBS solution (negative control animals) and wherein animals have EL-l ⁇ -induced NF- ⁇ B activation without any compound present [Vehicle/PL- l ⁇ ] or with increasing doses (0.3 mpk, 1 mpk, 3 mpk, and 10 mpk) of Compound (A) or Compound (B).
  • FIGURE 2 shows a graph of mouse imaging studies in the NF- ⁇ B-Luciferase Reporter Mouse Model showing bioluminescence levels for animals treated with the Vehicle/PBS solution (negative control animals) and wherein animals have IL-l ⁇ -induced NF- ⁇ B activation without any compound present [Vehicle/JL-l ⁇ ] or with increasing doses (0.3 mpk, 1 mpk, 3 mpk, and 10 mpk) of Compound (A) or Compound (B).
  • FIGURE 3 shows a graph of Compound (A) levels after i.t.
  • FIGURE 4 on the left, shows a graph of the lung exposure of Compound (A) after administering increasing doses (0.01 mpk, 0.03 mpk, 0.10 mpk, and 0.30 mpk) of Compound (A); and on the right, shows a graph of the plasma exposure of Compound (A) after administering increasing doses (0.01 mpk, 0.03 mpk, 0.10 mpk, and 0.30 mpk) of Compound (A).
  • FIGURE 5 on the left, shows a graph of the lung exposure of Compounds (A) and (B) after administering increasing doses (0.01 mpk, 0.03 mpk, 0.10 mpk, and 0.30 mpk) of Compound (B); and on the right, shows a graph of the plasma exposure of Compounds (A) and (B) after s administering increasing doses (0.01 mpk, 0.03 mpk, 0.10 mpk, and 0.30 mpk) of Compound (B).
  • Compound of the invention means the compound of formula (A), as hereinbefore described, which expression includes the pharmaceutically acceptable salt and the solvate, e.g., hydrate.
  • reference to intermediates, whether or not they themselves are claimed, is meant to embrace the salts, and solvates, where the context so permits.
  • particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and they are not intended to exclude other instances when the context so permits.
  • Treating means prevention, partial alleviation, or cure of the disease.
  • the compound and compositions of this invention are useful in treating conditions that are characterized by the activation of NF- ⁇ B and/or enhanced levels of cytokines and mediators that are regulated by NF- ⁇ B including, but not limited to TNF ⁇ and IL-l ⁇ . Inhibition or suppression of NF- ⁇ B and/or NF- ⁇ B- regulated genes such as TNF ⁇ may occur locally, for example, within certain tissues of the subject, or more extensively throughout the subject being treated for such a disease.
  • NF- ⁇ B-associated condition refers to diseases that are characterized by activation of NF- ⁇ B in the cytoplasm (e.g., upon phosphorylation of IKB).
  • TNF ⁇ -associated condition is a condition characterized by enhanced levels of TNF ⁇ . In the instant specification, the term NF- ⁇ B -associated condition will include a TNF ⁇ -associated condition but is not limited thereto as NF- ⁇ B is involved in the activity and upregulation of other pro-inflammatory proteins and genes.
  • inflammatory or immune diseases or disorders is used herein to encompass both NF- ⁇ B-associated conditions and TNF ⁇ -associated conditions, e.g., any condition, disease, or disorder that is associated with release of NF- ⁇ B and/or enhanced levels of TNF ⁇ , including conditions as described herein.
  • Patient includes both human and other mammals.
  • “Pharmaceutically effective amount” is meant to describe an amount of a compound, composition, medicament or other active ingredient effective in producing the desired therapeutic effect.
  • substantially pure is meant to refer to the compound where it is substantially free of biological or chemical constituents, e.g., isolated from a biological or chemical composition where biological or chemical components are co-isolated therewith, and wherein the analytical purity for the compound is preferably at least 70%. More preferred is where the analytical purity is at least 90%; even further preferred is where the analytical purity is at least 95%; also “substantially pure” is meant to refer to the compound where it is substantially free of prodrugs, e.g., Compound (B).
  • the invention also relates to a process for preparing the compound of the formula (A), as shown in the following Scheme.
  • Compounds such as carbonyldiimidazole, carbodiimides such as dicyclohexylcarbodiimide or diisopropylcarbodiimide (DIC), O- ((cyano (ethoxycarbonyl)methylene)-amino)-N, N, N ⁇ N'-tetramethyluronium tetrafluoroborate (TOTU) or polyphosphoric acid (PPA) are suitable for use as condensing agents or coupling reagents.
  • the condensations can be carried out under standard conditions. In the condensation, it is necessary for the non-reacting amino groups that are present to be protected with reversible protecting groups.
  • carboxyl groups that are not involved in the reaction with these groups preferably being present, during the condensation, as (C ⁇ -C 6 )-alkyl esters, benzyl esters or tert-butyl esters.
  • An amino group protection is not necessary if the amino groups are still present in the form of precursors such as nitro groups or cyano groups and are only formed by hydrogenation after the condensation.
  • the protecting groups that are present are eliminated in a suitable manner. For example, NO 2 groups (guanidino protection in amino acids), benzyloxycarbonyl groups and benzyl groups in benzyl esters can be eliminated by hydrogenation.
  • the protecting groups of the tert-butyl type are eliminated under acidic conditions while the 9-fluorenylmethyloxy-carbonyl radical is removed using secondary amines.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically effective amount of the compound of the formula (A) and a pharmaceutically acceptable carrier.
  • the compound according to the invention is suitable for the treatment of all those patients suffering from or subject to conditions that can be ameliorated by the targeted administration of an inhibitor of IKB kinase to a site where the treatment is better effected by localized versus systemic activity, e.g., asthma, or chronic obstructive pulmonary disorder (COPD).
  • an inhibitor of IKB kinase to a site where the treatment is better effected by localized versus systemic activity, e.g., asthma, or chronic obstructive pulmonary disorder (COPD).
  • COPD chronic obstructive pulmonary disorder
  • the compound of the present invention may be administered in pharmaceutically acceptable dosage form to humans and other animals by topical or systemic administration, including oral, inhalational, rectal, nasal, buccal, sublingual, vaginal, colonic, parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), intracistemal and intraperitoneal. It will be appreciated that the preferred route may vary with for example the condition of the recipient.
  • Intranasal, intratracheal, or inhalational administration, as well as aerosolization, are particular methods of administering the compound according to the invention.
  • Combination therapies may improve efficacy and decrease the risk of side effects compared with increasing the dose of a single agent.
  • IKK inhibitors can be combined with bronchodilators including but not limited to short-acting ⁇ 2-agonists; long-acting ⁇ 2-agonists such as salmeterol and formoterol; anticholinergic agents such as ipratropium bromide and tiotropium bromide.
  • IKK inhibitors can also be combined with methylxanthines such as theophylline.
  • Inhibitors of D K2 can be combined with several anti-inflammatory therapies including but not limited to immunomodulators directed at various stages of the inflammatory cascade and directed to ameliorating inflammatory processes.
  • Such therapies include, but are not limited to:
  • Inhibitors of cellular recruitment and toxic inflammatory mediators including but not limited to phosphodiesterase-4 inhibitors; inhibitors of p38 mitogen-activated protein kinase; biopharmaceuticals such as anti-tumor necrosis factor-alpha, anti-interleukin-8, and anti-monocyte chemoattractant protein- 1; inhibitors of adhesion molecules and chemotactic factors; and molecules that interfere with cell survival and clearance/apoptosis;
  • Inhibitors of proteolytic enzymes including but not limited to inhibitors of neutrophil-derived serine proteases such as neutrophil elastase; and inhibitors of matrix metalloproteinases (MMPs) such as MMP-2, MMP-9 and MMP-12;
  • MMPs matrix metalloproteinases
  • Antioxidants including but not limited to N-acetylcysteine and inhibitors or scavengers of reactive oxygen species; and toxic peptides such as defensins that can directly cause cell injury;
  • Inhibitors of mucus production including but not limited to inhibitors of mucous genes; and also mucus clearing agents such as expectorants, mucolytics, and mucokinetics; and
  • the drug combinations of the present invention can be provided to a cell or cells, or to a human patient, either in separate pharmaceutically acceptable formulations administered simultaneously or sequentially, formulations containing more than one therapeutic agent, or by an assortment of single agent and multiple agent formulations. However administered, these drug combinations form a pharmaceutically effective amount of components.
  • the treatment regimen/dosing schedule can be rationally modified over the course of therapy so that the lowest amounts of each of the pharmaceutically effective amount of compounds used in combination which together exhibit satisfactory pharmaceutical effectiveness are administered, and so that administration of such pharmaceutically effective amount of compounds in combination is continued only so long as is necessary to successfully treat the patient.
  • a pharmaceutical composition according to the invention is preferably produced and administered in dosage units, with each unit containing, as the active constituent, a particular dose of the compound.
  • Pharmaceutically acceptable salts of the compound of formula (A) are within the scope of this invention.
  • the term “salt(s)” means acid or base addition salts formed with acids and bases.
  • the term “salt(s)” include zwitterion salts (inner salts), i.e., as the compound of formula (A) contains both a basic moiety, such as an amine or a pyridine or imidazole ring, and an acidic moiety, such as a carboxylic acid.
  • Salts of the compounds of the formula (A) may be formed, for example, by reacting a compound of the formula (A) with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Acid addition salts are formed with the compound of the invention bearing basic moiety(ies) such as an imino nitrogen, amino or mono or disubstituted group is present.
  • Particular acid addition salts are the pharmaceutically acceptable acid addition salts, i.e., salts whose anion is non-toxic to a patient at a pharmaceutical dose of the salt, and so that the beneficial effects inherent in the free form of the compound are not vitiated by side effects ascribable to the anion.
  • the salts chosen are chosen optimally to be compatible with the customary pharmaceutical vehicles and adapted for the form of applicable administration.
  • Acid addition salts of the compound of this invention can be prepared by reaction of the free form of the molecule bearing the basic moiety with the appropriate acid, by the application or adaptation of known methods.
  • the acid addition salts of the compound of this invention can be prepared either by dissolving the free form of the molecule bearing the base moiety in water or aqueous alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free form of the molecule bearing the base moiety and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
  • acids for use in the preparation of such salts are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, various organic carboxylic and sulfonic acids, such as acetic acid, citric acid, propionic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid, malic acid, methanesulfonic acid, toluenesulfonic acid, mandelic acid, ascorbic acid, malic acid, fatty acids, adipate alginate, ascorbate, aspartate, benzenesulfonate, benzoate, cyclopentanepropionate, digluconate, dodecylsulfate, bisulfate, butyrate, lactate, laurate, lauryl sulfate, maleate, hydroiodide, 2-hydroxy-ethanesulfonate, glycerophosphate, picrate, pivalate, palmoate,
  • the acid addition salts of the compound of this invention can also be used to regenerate the parent compound of the invention from the salts by the application or adaptation of known methods.
  • the parent compound of the invention can be regenerated from their acid addition salts by treatment with an alkali, e.g., aqueous sodium bicarbonate solution or aqueous ammonia solution.
  • Base addition salts are formed with the compound of the invention bearing the carboxy moiety.
  • Particular base addition salts are the pharmaceutically acceptable base addition salts, i.e., salts whose cation is non-toxic to a patient at a pharmaceutical dose of the salt, so that the beneficial effects inherent in the free form of the compound are not vitiated by side effects ascribable to the anion.
  • the salts chosen are chosen optimally to be compatible with the customary pharmaceutical vehicles and adapted for the form of applicable administration.
  • Base addition salts of the compound of this invention can be prepared by reaction of the free form of the molecule bearing the acid moiety with the appropriate base, by the application or adaptation of known methods.
  • the base addition salts of the compound of this invention can be prepared either by dissolving the free form of the molecule bearing the acid moiety in water or aqueous alcohol solution or other suitable solvents containing the appropriate base and isolating the salt by evaporating the solution, or by reacting the free form of the molecule bearing the acid moiety and base in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
  • Suitable bases for use in the preparation of such salts are those derived from alkali and alkaline earth metal salts or amines such as: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl- glucamine, lysine, arginine, ornithine, choline.
  • N,N'-dibenzylethylenediamine chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)- aminomethane, tetramethylammonium hydroxide, and the like.
  • the base addition salts of the compound of this invention can also be used to regenerate the parent compound of the invention from the salts by the application or adaptation of known methods.
  • the parent compound of the invention can be regenerated from their base addition salts by treatment with an acid, e.g., hydrochloric acid.
  • the compound of the present invention is administered in a suitable formulation to patients such that its activity is particularly localized. It will be appreciated that the preferred route can be varied depending on the site of the condition for which administration is directed.
  • Pharmaceutically acceptable dosage forms refers to dosage forms of the compound of the invention, and includes, for example, powders, suspensions, sprays, inhalants, tablets, emulsions, and solutions, particularly suitable for inhalation. Techniques and formulations generally may be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, latest edition.
  • the compound can be microencapsulated in, or attached to, a slow release or targeted delivery systems such as biocompatible, biodegradable polymer matrices (e.g., poly(d,l-lactide co-glycolide)), liposomes, and microspheres and subcutaneously or intramuscularly injected by a technique called subcutaneous or intramuscular depot to provide continuous slow release of the compound(s) for a period of 2 weeks or longer.
  • a slow release or targeted delivery systems such as biocompatible, biodegradable polymer matrices (e.g., poly(d,l-lactide co-glycolide)), liposomes, and microspheres and subcutaneously or intramuscularly injected by a technique called subcutaneous or intramuscular depot to provide continuous slow release of the compound(s) for a period of 2 weeks or longer.
  • a slow release or targeted delivery systems such as biocompatible, biodegradable polymer matrices (e.g., poly(d,l-lactide
  • the compound may also be sterilized, for example, by filtration through a bacteria retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile medium immediately before use.
  • Formulations suitable for nasal or tracheal administration means formulations that are in a form suitable to be administered nasally or by inhalation to a patient.
  • the formulation may contain a carrier, in a powder form, having a particle size for example in the range 1 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc.).
  • Suitable formulations wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents. MDI and DPI are feasible means for effecting inhalation therapy by administering a dosage form of the compound of the present invention.
  • Actual dosage levels of active ingredient(s) in the compositions of the invention may be varied so as to obtain an amount of active ingredient(s) that is (are) effective to obtain a desired therapeutic response for a particular composition and method of administration for a patient.
  • a selected dosage level for any particular patient therefore depends upon a variety of factors including the desired therapeutic effect, on the route of administration, on the desired duration of treatment, the etiology and severity of the disease, the patient's condition, weight, sex, diet and age, the type and potency of each active ingredient, rates of absorption, metabolism and/or excretion and other factors.
  • the daily dose can be administered either by means of a once-only administration in the form of a single dosage unit, or of several smaller dosage units, or by means of the multiple administration of subdivided doses at predetermined intervals.
  • the percentage of active ingredient in a composition may be varied, though it should constitute a proportion such that a suitable dosage shall be obtained.
  • several unit dosage forms can be administered at about the same time. A dosage may be administered as frequently as necessary in order to obtain the desired therapeutic effect.
  • Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate.
  • it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. It goes without saying that, for other patients, it will be necessary to prescribe not more than one or two doses per day.
  • the formulations can be prepared in unit dosage form by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier that constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Mass-spectroscopic methods (FAB-MS, ESI-MS) are used for analyzing. Temperatures are given in degrees Celsius; RT denotes room temperature (from 22°C to 26°C). Abbreviations used are either explained or correspond to customary conventions to one skilled in the art.
  • the invention is exemplified through the following Examples.
  • Methyl 2-(di-tert-butoxycarbonylamino)acrylate (Scheme 1, Compound 2) 50 g (0.228 mol) of (tert-butoxycarbonyl)serine (V) were dissolved in 300 mL of acetonitrile. 107 g (0.493 mol) of di-tert-butyl dicarbonate and 2.64 g (22 mmol) of 4-(dimethylamino)pyridine (DMAP) were added. The mixture was stirred at room temperature overnight, after which the solvent was removed under reduced pressure and the residue was taken up in 500 mL of ethyl acetate.
  • DMAP 4-(dimethylamino)pyridine
  • the organic phase was washed with 500 mL of 1 N HCl, dried using magnesium sulfate and the organic solvents were removed under reduced pressure.
  • 23 g of acrylate 2 were obtained by crystallizing the residue from 200 mL of heptane at -30°C and then filtering with suction.
  • the mother liquor was concentrated and the residue was dissolved in 140 mL of acetonitrile.
  • 31 g (0.142 mol) of di-tert-butyl dicarbonate and 1.26 g (10 mmol) of DMAP were added. After the mixture had been heated at 50°C for 8 h, the solvent was removed in vacuo and the residue was taken up in 500 mL of ethyl acetate.
  • Racemic amino ester 3 was prepared from the corresponding acrylic ester 2 and then resolved into enantiomers 3(S) and 3(R) by means of preparative HPLC using chiral stationary phases such as Chiralpak AD (Daicel) 100 x 380, RT, flow rate 300 mL/min. The purity of the enantiomers were determined by analytical HPLC such as Chiralpak-AD-H (Daicel) 4.6 x 250, 30°C, flow rate 1 ml/min, room temperature.
  • the assay buffer has the following composition (50 mM HEPES, 10 mM MgC12, 10 mM ⁇ - Glycerophosphate, 2 ⁇ M Microcystin-LR, 0,01% NP-40, 5 mM DTT).
  • the IKK enzyme preparation was diluted 1:50 (in-house-made preparation) plus test compound in DMSO (final concentration in well: 2 %).
  • the assay procedures were as follows: Incubation of enzyme and compound for 30 min; Addition of ImM ATP or 50 ⁇ M ATP; pSer36-IkB Peptide (Substrate): 40 ⁇ M; Incubation for 45 min and Addition of anti- pSer32-pSer36-IkB Peptid -antibody; Incubation for 45 min and transfer to protein-G-coated plate; Incubation for 90 min followed by 3x washing; Addition of streptavidin-HRP, then incubation 45 min followed by 6x washing; Addition of TMB and Incubation for 15 min; and Stop solution and read using photometer.
  • Table I The results from the in vitro profiling are shown in Table I below. Table I
  • I ⁇ B kinase IKK is the converging point for the activation of NF- ⁇ B by a broad spectrum of inflammatory agonists.
  • IKK is a multisubunit complex that contains two catalytic subunits, IKK-1 (also known as IKK- ⁇ ) and IKK-2 (also known as IKK- ⁇ ), and the regulatory subunit IKK- ⁇ .
  • IKK-2 or IKK- ⁇ subunits of the IKK complex are required for NF- ⁇ B activation by all known pro-inflammatory stimuli including lipopolysaccharide (LPS), and IL-l ⁇ .
  • LPS lipopolysaccharide
  • IL-l ⁇ interleukin-l ⁇
  • Intranasal drug and inflammatory stimulus administration Mice are anesthetized in 4% isoflurane gas in oxygen. A volume of 25 ⁇ l is applied to each nostril and the mice are allowed to breathe in the suspension.
  • mice at 6-8 weeks of age were used for studies in which AdV-NF ⁇ B-lucif erase reporter was instilled in the lung.
  • To image mice they are anesthetized with 4% isoflurane in oxygen. Luciferin is delivered i.p. at a dose of 150 mg/kg. 10 minutes after luciferin injection, the animals are imaged in an IVIS200 system (Xenogen) with a one-minute bioluminescent exposure. Alternatively, 10-15 minutes post luciferin administration, mice are rapidly euthanized and internal tissues are dissected and imaged ex vivo.
  • Nanomilled suspensions of Compound (A) and Compound (B) were dosed via intra-tracheal instillation at 0.01, 0.03, 0.1 and 0.3mg/kg.
  • animals were euthanized (Euthasol), and 1 mL blood samples were obtained by cardiac puncture and collected into heparin-coated syringes.
  • Plasma was separated from the cellular component of the blood by centrifugation, and stored at -80°C until assayed.
  • Lungs were dissected out, blotted dry, weighted and stored in 20-25 mL glass vials individually at -80°C until assayed for compound levels.
  • Figure 3 shows that lung exposure to either Compound (A) or Compound (B) after i.t. instillation of Compound (B) is low relative to Compound (A) after i.t. administration, suggesting that Compound (B) is rapidly absorbed from the lung.
  • Figures 3 to 5 also show that Compound (B) would be a weaker candidate for inhalation because 1) It is highly systemically distributed upon exposure, when administered intratracheally; 2) Compound (B) is a prodrug of Compound (A) having a different exposure profile; and 3) Compound (B) produces reduced exposure to Compound (A) in the lung than is obtained by dosing directly with Compound (A).
  • Compound (A) is a stronger inhalation candidate than Compound (B) because 1) Compound (A) has low systemic exposure after i.t. and PO administration; and 2) Compound (A) should have longer lung residency time.
  • Compound (B) is highly systemically available when administered orally.
  • the lung to plasma ratio for Compound (A) ranges from 143 to 284 (depending on the dose) whereas the lung to plasma ratio for Compound (B) ranges from 13 to 44 (depending on the dose). These ratios were obtained by dividing the lung compound levels to that of the corresponding plasma levels at the same dose.

Abstract

La présente invention est destinée au composé substantiellement pur de formule (A) ou à un sel pharmaceutiquement acceptable ou un solvat dudit composé ; à une composition pharmaceutique comprenant la quantité pharmaceutiquement efficace du composé de formule (A) et un vecteur pharmaceutiquement acceptable ; l'utilisation d'un composé de formule (A) ayant une activité d'inhibiteur, de préférence un inhibiteur sélectif, de IkB (IKK), en particulier IKK-2 et les méthodes liées à cela.
PCT/US2005/016381 2004-05-12 2005-05-11 2-{[2-(2-méthylamino-pyrimidine-4-yl)-1h-indole-5-carbonyle]-aminé}-3-(phénylpyridine-2-yl-aminé)-acide propionique substantiellement pur comme inhibiteur de kinase ikb WO2005113544A1 (fr)

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MXPA06012870A MXPA06012870A (es) 2004-05-12 2005-05-11 Acido 2-{[2-(2- metilaminopirimidin -4-il)-1h- indol-5 -carbonil]amino}-3 -(fenilpiridin -2-ilamino) propionico sustancialmente puro como inhibidor de la cinasa ikb.
CA002566213A CA2566213A1 (fr) 2004-05-12 2005-05-11 2-{[2-(2-methylamino-pyrimidine-4-yl)-1h-indole-5-carbonyle]-amine}-3-(phenylpyridine-2-yl-amine)-acide propionique substantiellement pur comme inhibiteur de kinase ikb
AU2005245834A AU2005245834A1 (en) 2004-05-12 2005-05-11 Substantially pure 2-{[2-(2-methylamino-pyrimidin-4-yl)-1h-indole-5-carbonyl]-amino}-3-(phenylpyridin-2-yl-amino)-propionic acid as an ikB kinase inhibitor
JP2007513292A JP2007537266A (ja) 2004-05-12 2005-05-11 ＩκＢキナーゼ阻害剤として実質的に純粋な２−｛［２−（２−メチルアミノ−ピリミジン−４−イル）−１Ｈ−インドール−５−カルボニル］−アミノ｝−３−（フェニルピリジン−２−イル−アミノ）−プロピオン酸
BRPI0511029-7A BRPI0511029A (pt) 2004-05-12 2005-05-11 ácido 2-{[2-(2-metil amino-pirimidin-4-il)-1h-indol-5-carbonil]-amino}-3-(feni l piridin-2-il-amino)-propiÈnico substancialmente puro como um inibidor da i capa b quinase
EP05749733A EP1747215A1 (fr) 2004-05-12 2005-05-11 2-{¬2-(2-MÉTHYLAMINO-PYRIMIDINE-4-YL)-1H-INDOLE-5-CARBONYLE|-AMINÉ}-3-(PHÉNYLPYRIDINE-2-YL-AMINÉ)-ACIDE PROPIONIQUE SUBSTANTIELLEMENT PUR COMME INHIBITEUR DE KINASE IKB
TNP2006000338A TNSN06338A1 (en) 2004-05-12 2006-10-18 Substantially pure 2-{[2-(2-methylamino-pyrimidin-4-yl)-1h-indole-5-carbonyl]-amino}-3-(phenylpyridin-2-yl-amino)-propionic acid as an ikb kinase inhibitor
IL178992A IL178992A0 (en) 2004-05-12 2006-11-01 Substantially pure 2-{[2-(2-methylamino-pyrimidin-4-yl)-1h-indole-5-carbonyl]-amino}-3-
US11/559,159 US20070142417A1 (en) 2005-05-11 2006-11-13 Substantially Pure 2-{[2-(2-Methylamino-Pyrimidin-4-YL)-1H-Indole-5-Carbonyl]-Amino}-3-Phenylpyridin-2-YL-Amino)-Propionic Acid as an IkB Kinase Inhibitor
NO20065719A NO20065719L (no) 2004-05-12 2006-12-12 I det vesentlige rene 2-{[2-(2-metylamino-pyrimidin-4-yl)-1H-indol-5-karbonyl]-amlno}-3-(fenylpyridin-2-yl-amino)-propionsyre som en IkB kinaseinhibitor.

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JP2008505860A (ja) * 2004-07-10 2008-02-28 サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング ２，３−ジアミノプロピオン酸誘導体のエナンチオマー体の製造方法。
US7342029B2 (en) 1999-10-26 2008-03-11 Sanofi-Aventis Deutschland Gmbh Substituted indoles
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2009132050A2 (fr) 2008-04-21 2009-10-29 Otonomy, Inc. Préparations auriculaires de traitement de maladies et états otiques
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011134140A1 (fr) * 2010-04-27 2011-11-03 Hutchison Medipharma Limited Pyrimidinylindoles
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
US10821185B2 (en) 2016-06-29 2020-11-03 Otonomy Inc. Triglyceride otic formulations and uses thereof
US11969501B2 (en) 2008-04-21 2024-04-30 Dompé Farmaceutici S.P.A. Auris formulations for treating otic diseases and conditions

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WO2004022553A1 (fr) * 2002-08-17 2004-03-18 Aventis Pharma Deutschland Gmbh DERIVES D'INDOLE OU DE BENZIMIDAZOLE POUR MODULER L'IλB KINASE

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US7342029B2 (en) 1999-10-26 2008-03-11 Sanofi-Aventis Deutschland Gmbh Substituted indoles
US8053590B2 (en) 2004-07-10 2011-11-08 Sanofi-Aventis Deutschland Gmbh Method for producing enantiomeric form of 2,3-diaminopropionic acid derivatives
JP4861317B2 (ja) * 2004-07-10 2012-01-25 サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング ２，３−ジアミノプロピオン酸誘導体のエナンチオマー体の製造方法。
JP2008505860A (ja) * 2004-07-10 2008-02-28 サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング ２，３−ジアミノプロピオン酸誘導体のエナンチオマー体の製造方法。
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
US10751281B2 (en) 2008-04-21 2020-08-25 Otonomy, Inc. Auris formulations for treating otic diseases and conditions
US10272034B2 (en) 2008-04-21 2019-04-30 Otonomy, Inc. Auris formulations for treating otic diseases and conditions
US11969501B2 (en) 2008-04-21 2024-04-30 Dompé Farmaceutici S.P.A. Auris formulations for treating otic diseases and conditions
US11123285B2 (en) 2008-04-21 2021-09-21 Otonomy, Inc. Auris formulations for treating OTIC diseases and conditions
WO2009132050A2 (fr) 2008-04-21 2009-10-29 Otonomy, Inc. Préparations auriculaires de traitement de maladies et états otiques
US11123286B2 (en) 2008-04-21 2021-09-21 Otonomy, Inc. Auris formulations for treating otic diseases and conditions
US9132087B2 (en) 2008-04-21 2015-09-15 Otonomy, Inc. Auris formulations for treating otic diseases and conditions
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
US8501166B2 (en) 2010-04-27 2013-08-06 Hutchison Medipharma Limited Pyrimidinyl indole compounds
WO2011134140A1 (fr) * 2010-04-27 2011-11-03 Hutchison Medipharma Limited Pyrimidinylindoles
RU2552999C2 (ru) * 2010-04-27 2015-06-10 Хатчисон Медифарма Лимитед Соединения пиримидинилиндола
AU2010351938B2 (en) * 2010-04-27 2014-10-30 Hutchison Medipharma Limited Pyrimidinyl indole compounds
TWI410419B (zh) * 2010-04-27 2013-10-01 Hutchison Medipharma Ltd 嘧啶基吲哚化合物
JP2013525381A (ja) * 2010-04-27 2013-06-20 ハチソン メディファーマ リミテッド ピリミジニルインドール化合物
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
US10821185B2 (en) 2016-06-29 2020-11-03 Otonomy Inc. Triglyceride otic formulations and uses thereof

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UY28897A1 (es) 2005-12-30
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EP1747215A1 (fr) 2007-01-31
RU2006143758A (ru) 2008-06-27

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